Substituted imidazo [1,2-a] pyridine derivatives

ABSTRACT

The present invention is a series of novel compounds of formula I and a method of treatment or prevention of a mGluR5 receptor mediated disease by administering an therapeutically effective amount of a compound formula 
                 
 
wherein R 1  and R 2  are selected from hydrogen, (C 1-6 )-alkyl, halogen, hydroxy, (C 1-6 )-alkoxy and A is defined the description, or a pharmaceutically acceptable salt thereof.

This is a divisional application of U.S. patent application Ser. No.10/093,790, filed Mar. 8, 2002 now U.S Pat. No. 6,596,731.

BACKGROUND

The synthesis of some imidazo[1,2-a]pyridine derivatives is described inRecl. Trav. Chim. Pays-Bas 1949, 68, 441-470, in J. Org. Chem. 1954, 19,1370-1374, in J. Heterocyclic Chem. 1988, 25, 129-137, in Internationalpatent application WO 00/08021 or in J. Org. Chem. 2000, 65, 9201-9205.According to J. Prakt. Chem. 1971, 313, 977-985,imidazo[1,2,-a]pyridines bearing a benzothienyl, thienyl or benzofuranylgroup have been prepared by condensation of α-haloketones orα-hydroxyketones with amidines. The synthesis and antimicrobial actionof furyl derivatives of imidazo[1,2-a]pyrimidine is reported inKhim.-Farm. Zh. 1970, 4, 20-26.

Different uses have been described for imidazo[1,2-a]pyridinederivatives. The preparation of2-[p-(dimethylamino)phenyl]-imidazo[1,2-a]pyridine as an azo dye and itsevaluation as disperse dye on synthetic fibers, cellulose acetate, andcotton is described in Boll. Sci. Fac. Chim. Ind. Bologna 1966, 24,205-214. Fluorescent properties of imidazo[1,2-a]-pyridine-basedcompounds are described in Bull. Chem. Soc. Jpn. 1999, 72(6), 1327-1334.Japanese patent applications JP 50-140477, JP 51-004194 and JP 51-125095report the analgesic, antiinflammatory, antipyretic, and localanesthetic activities of certain phenyl-imidazo[1,2-a]pyridines whereinthe phenyl ring is substituted by —CR¹R²COOH, —CR¹R²COOR, —CR¹R²CONH₂,—CR¹R²CSNH₂, —CR¹R²CN, —CO₂—(CH₂)₁₋₄—NR³R⁴ or —CH₂OH and R, R¹, R², R³,and R⁴ are hydrogen or alkyl. According to Arzneim.-Forsch. 1981, 31(7),1111-1118, the most preferred compound thereof, viz.4-imidazo[1,2-a]pyridin-2-yl-α-methyl-benzeneacetic acid (miroprofen) iseffective in suppressing pain responses and acute inflammationaccompanied by increased vascular permeability. The use ofimidazo[1,2-a]pyridines substituted at the 2 and 6 positions asanthelmintic and fungicidal agents is disclosed in U.S. Pat. No.3,701,780. Isothiocyanato derivatives like2-(4-isothiocyanato-phenyl)-6-methyl-imidazo[1,2-a]pyridine aredescribed as antihelmintics in Swiss patent No. CH 590 862.

The use of imidazo[1,2-a]pyridine derivatives as inhibitors for STAT6 6transcription factor activation and IL 4 antagonists for treatment ofallergic, autoimmune, parasital, viral, and bacterial diseases, tumors,host-vs. graft syndrome, systemic lupus erythematosus, and AIDS isdisclosed in Japanese patent application No. JP 11-116481.

According to Eur. J. Med. Chem. 1994, 29(5), 339-342, aryl- orpyridyl-substituted fused imidazoles such as2-(4-pyridinyl)-imidazo[1,2-a]pyridine, possess cardiotonic activity.N-(4-imidazo[1,2-a]pyridin-2-yl-phenyl)-methanesulfonamide has beenprepared and is reported as an antithrombotic and cardiovascular agentin European patent application EP 0 185 345. According to Eur. J. Med.Chem. 1987, 22(5), 457-462, certain imidazo[1,2-a]pyrimidines, e.g.2-(2-furanyl)-imidazo[1,2-a]pyridine, were tested for bronchodilatoractivity and for inhibition of a cardiac phosphodiesterase. Phosphonicacid derivatives of imidazo[1,2-a]pyridines, e.g.[5-(6-chloroimidazo[1,2-a]pyridin-2-yl)-2-furanyl]-phosphonic acid, aredescribed as human liver fructose-1,6-bisphosphatase inhibitors inInternational patent application WO 98/39342.

N,N,6-trimethyl-2-(4-methylphenyl)-imidazo[1,2-a]pyridine-3-acetamide(Zolpidem) and its use as anticonvulsant and hypnotic was firstdisclosed in European patent application EP 0 050 563. Furtherimidazo[1,2-a]pyridine derivatives with anticonvulsant, hypnotic andanxiolytic activity are also described in the patent applications EP 0092 458, EP 0 092 459, EP 0 172 096, FR 25 81 646, EP 0 234 970, EP 0251 859 and EP 0 267 111. Eur. J. Pharmacol. 1986, 130(3), 257-263,reports that Zolpidem possesses agonist properties at centralbenzodiazepine receptors and according to Br. J. Pharmacol. 2000,131(7), 1251-1254 the mechanism of action of Zolpidem in vivo is basedon its high affinity to the α1-GABAA receptor benzodiazepine site.

SUMMARY

The present invention is a method of treating a disease responsive tomediating the mGluR5 receptor by administering, to a person in need ofsuch treatment, a therapeutically effective amount of a compound offormula

wherein

-   -   R¹ is selected from the group consisting of hydrogen,        (C₁₋₆)-alkyl, halogen, hydroxy and (C₁₋₆)-alkoxy;    -   R² is selected from the group consisting of hydrogen,        (C₁₋₆)-alkyl, halogen, hydroxy and (C₁₋₆)-alkoxy; and    -   A is unsubstituted aryl or aryl substituted with at least one        substituent selected from the group consisting of (C₁₋₆)-alkyl,        halogen, halogen-(C₁₋₆)-alkyl, hydroxy, (C₁₋₆)-alkoxy,        benzyloxy, amino, (C₁₋₆)-alkylamino, di-(C₁₋₆)-alkyl-amino,        arylamino, diarylamino and nitro, or is unsubstituted heteroaryl        or heteroaryl substituted with at least one substituent selected        from the group consisting of (C₁₋₆)-alkyl, halogen,        halogen-(C₁₋₆)-alkyl, hydroxy, (C₁₋₆)-alkoxy, benzyloxy, amino,        (C₁₋₆)-alkylamino, di-(C₁₋₆)-alkyl-amino, arylamino, diarylamino        and nitro or signifies the group        wherein    -   X_(a) and X_(b) are, independently from each other, selected        from the group consisting of —CH₂— and —O—; and    -   n is 1 or 2;    -   or a pharmaceutically acceptable salt thereof.

It has now surprisingly been found that the compounds of formula I aremetabotropic glutamate receptor antagonists. Compounds of formula I aredistinguished by having valuable therapeutic properties. These compoundscan be used in the treatment or prevention of mGluR5 receptor mediateddisorders.

In the central nervous system (CNS) the transmission of stimuli takesplace by the interaction of a neurotransmitter, which is sent out by aneuron, with a neuroreceptor.

Glutamate is the major excitatory neurotransmitter in the brain andplays a unique role in a variety of central nervous system (CNS)functions. The glutamate-dependent stimulus receptors are divided intotwo main groups. The first main group, namely the ionotropic receptors,forms ligand-controlled ion channels. The metabotropic glutamatereceptors (mGluR) belong to the second main group and, furthermore,belong to the family of G-protein coupled receptors.

At present, eight different members of these mGluR receptors are knownand some of these even have sub-types. According to their sequencehomology, signal transduction mechanisms and agonist selectivity, theseeight receptors can be sub-divided into three sub-groups: mGluR1 andmGluR5 belong to group I, mGluR2 and mGluR3 belong to group II andmGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.

Ligands of metabotropic glutamate receptors belonging to the first groupcan be used for the treatment or prevention of acute and/or chronicneurological disorders such as psychosis, epilepsy, schizophrenia,Alzheimer's disease, cognitive disorders and memory deficits, as well aschronic and acute pain.

Other treatable indications in this connection are restricted brainfunction caused by bypass operations or transplants, poor blood supplyto the brain, spinal cord injuries, head injuries, hypoxia caused bypregnancy, cardiac arrest and hypoglycaemia. Further treatableindications are ischemia, Huntington's chorea, amyotrophic lateralsclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy,idiopathic parkinsonism or parkinsonism caused by medicaments as well asconditions which lead to glutamate-deficiency functions, such as e.g.muscle spasms, convulsions, migraine, urinary incontinence, nicotineaddiction, opiate addiction, anxiety, vomiting, dyskinesia anddepressions.

Disorders mediated full or in part by mGluR5 are for example acute,traumatic and chronic degenerative processes of the nervous system, suchas Alzheimer's disease, senile dementia, Parkinson's disease,Huntington's chorea, amyotrophic lateral sclerosis and multiplesclerosis, psychiatric diseases such as schizophrenia and anxiety,depression and pain. Selective mGluR5 antagonists are especially usefulfor the treatment of anxiety and pain.

Objects of the present invention are the use of compounds of formula Iand their pharmaceutically acceptable salts for the manufacture ofpharmaceutical compositions for the treatment or prevention of mGluR5receptor mediated disorders, such as acute and/or chronic neurologicaldisorders, cognitive disorders and memory deficits such as Alzheimer'sdisease, senile dementia, Parkinson's disease, ischemia, Huntington'schorea, amyotrophic lateral sclerosis and multiple sclerosis,psychiatric diseases such as psychosis, epilepsy, schizophrenia, anxietyand depression as well as chronic and acute pain.

DETAILED DESCRIPTION

The following definitions of general terms used in the presentdescription apply irrespective of whether the terms in question appearalone or in combination. The term “(C₁₋₆)-alkyl” used in the presentdescription denotes straight-chain or branched saturated hydrocarbonresidues with 1 to 6 carbon atoms, preferably with 1 to 4 carbon atoms,such as methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl and thelike.

The term “halogen” denotes fluorine, chlorine, bromine and iodine.

The term “halogen-C₁₋₆)-alkyl” denotes C₁₋₆)-alkyl, wherein the hydrogenatoms are replaced by one or more halogen atoms.

The term “(C₁₋₆)-alkoxy” denotes a (C₁₋₆)-alkyl group as definedhereinbefore, which is bound via an oxygen atom, e.g. methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy and the like.

“Aryl” represents an aromatic carbocyclic group consisting of oneindividual ring, or one or more fused rings in which at least one ringis aromatic in nature. Preferred aryl groups are phenyl or naphthyl.

The term “heteroaryl” refers to an aromatic 5- or 6-membered ringcontaining one or more heteroatoms selected from nitrogen, oxygen orsulphur, or to a bicyclic aromatic group comprising two 5- or 6-memberedrings, in which one or both rings can contain one or more heteroatomsselected from nitrogen, oxygen or sulphur. Examples of such heteroarylgoups are furyl, pyrrolyl, thienyl (thiophenyl), 1H-imidazolyl,2H-imidazolyl, 4H-imidazolyl, 1H-pyrazolyl, 3H-pyrazolyl, 4H-pyrazolyl,1,2-oxazolyl, 1,3-oxazolyl, [1,2,4]triazolyl, [1,2,3]triazolyl,[1,2,4]oxadiazolyl, [1,3,4]oxadiazolyl, [1,2,3]oxadiazolyl, tetrazolyl,[1,2,3,4]oxatriazolyl, [1,2,3,5]oxatriazolyl, 1,3-thiazolyl,1,2-thiazolyl, pentazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,benzofuryl (benzofuranyl), benzothienyl (benzothiophenyl),benzimidazolyl, benzo[1,4]dioxinyl, benzoxazolyl, benzothiazolyl,indolyl, isoindolyl, quinolyl, isoquinolyl and their dihydroderivatives.

Preferred heteroaryl groups are thienyl, benzofuryl or benzothienyl.

The term “(C₁₋₆)-alkylamino” denotes a straight-chain or branched alkylchain having from one to six carbon atoms attached to an amino group.Examples of such (C₁₋₆)-alkylamino groups are methylamino, ethylamino,isopropylamino and the like. “Di-(C₁₋₆)-alkylamino” represents twostraight-chain or branched dialkyl chains having from one to six carbonatoms attached to an amino group. Examples of such di-(C₁₋₆)-alkylaminogroups are dimethylamino, ethylmethylamino and the like. “Arylamino”denotes an aryl group as defined above attached to an amino group. Aphenylamino group is an example of such a group.

The term “pharmaceutically acceptable salt” refers to any salt derivedfrom an inorganic or organic acid or base known to one skilled in theart as usable in a pharmaceutical preparation.

Preferred compounds of formula I for the above mentioned method oftreatment are those, in which A is unsubstituted aryl or arylsubstituted with at least one substituent selected from the groupconsisting of (C₁₋₆)-alkyl, halogen, halogen-(C₁₋₆)-alkyl, hydroxy,(C₁₋₆)-alkoxy, benzyloxy, amino, C₁₋₆)-alkylamino, di-C₁₋₆)-alkyl-amino,arylamino, diarylamino and nitro.

Especially preferred for the above mentioned method of treatment arethose compounds of formula I, in which A is unsubstituted phenyl orphenyl substituted with one or more substituents selected from the groupconsisting of (C₁₋₆)-alkyl, halogen, halogen-(C₁₋₆)-alkyl, hydroxy,(C₁₋₆)-alkoxy, benzyloxy, amino, (C₁₋₆)-alkylamino,di-(C₁₋₆)-alkylamino, arylamino, diarylamino or nitro.

Even more preferred for the above mentioned method of treatment arecompounds of formula I, in which A signifies phenyl substituted with onesubstituent selected from the group consisting of (C₁₋₆)-alkyl, halogen,halogen-C₁₋₆)-alkyl, hydroxy, C₁₋₆)-alkoxy, benzyloxy, amino,C₁₋₆)-alkylamino, di-(C₁₋₆)-alkyl-amino, arylamino, diarylamino ornitro. The following are examples of these more preferred compounds:

-   -   2-(3-bromo-phenyl)-imidazo[1,2-a]pyridine,    -   2-(3-iodo-phenyl)-imidazo[1,2-a]pyridine,    -   2-(3-chloro-phenyl)-imidazo[1,2-a]pyridine,    -   2-(3-methyl-phenyl)-imidazo[1,2-a]pyridine,    -   2-(3-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine,    -   2-(3-fluoro-phenyl)-imidazo[1,2-a]pyridine,    -   7-methyl-2-phenyl-imidazo[1,2-a]pyridine,    -   2-(4-methyl-phenyl)-imidazo[1,2-a]pyridine,    -   2-(3-methoxy-phenyl)-imidazo[1,2-a]pyridine,    -   6-methyl-2-(4-methyl-phenyl)-imidazo[1,2-a]pyridine, and    -   2-(3-nitro-phenyl)-imidazo[1,2-a]pyridine.

Further preferred are those compounds of formula I for the abovementioned method of treatment, in which A is phenyl substituted with atleast two substituents selected from the group consisting of(C₁₋₆)-alkyl, halogen, halogen-(C₁₋₆)-alkyl, hydroxy, (C₁₋₆)-alkoxy,benzyloxy, amino, (C₁₋₆)-alkylamino, di-(C₁₋₆)-alkylamino, arylamino,diarylamino and nitro.

Examples of these further preferred compounds are

-   -   7-chloro-2-(3,4-dimethyl-phenyl)-imidazo[1,2-a]pyridine,    -   2-(3,4-dimethoxy-phenyl)-7-methyl-imidazo[1,2-a]pyridine,    -   2-(3,4-dimethoxy-phenyl)-imidazo[1,2-a]pyridine,    -   2-(3,4-dimethyl-phenyl)-7-methoxy-imidazo[1,2-a]pyridine,    -   2-(3,4-dimethoxy-phenyl)-7-methoxy-imidazo[1,2-a]pyridine,    -   2-(3,4-dimethyl-phenyl)-imidazo[1,2-a]pyridine hydrochloride,    -   2-(3,4-dimethyl-phenyl)-7-methyl-imidazo[1,2-a]pyridine,    -   2-(3-bromo-4-fluoro-phenyl)-imidazo[1,2-a]pyridine,    -   2-(4-benzyloxy-3-methoxy-phenyl)-imidazo[1,2-a]pyridine,    -   2-(3,4-dimethyl-phenyl)-7-ethyl-imidazo[1,2-a]pyridine, or    -   2-(3,4-dimethoxy-phenyl)-6-methyl-imidazo[1,2-a]pyridine.

Also preferred for the above mentioned method of treatment are compoundsof formula I, in which A is unsubstituted heteroaryl or heteroarylsubstituted with at least one substituent selected from the groupconsisting of (C₁₋₆)-alkyl, halogen, halogen, —(C₁₋₆)-alkyl, hydroxy,C₁₋₆)-alkoxy, benzyloxy, amino, (C₁₋₆)-alkylamino, di-(C₁₋₆)-alkylamino,arylamino, diarylamino and nitro.

The following are examples of these also preferred compounds:

-   -   2-benzofuran-2-yl-imidazo[1,2-a]pyridine,    -   2-benzo[b]thiophen-3-yl-imidazo[1,2-a]pyridine,    -   2-(5-methyl-thiophen-2-yl)-imidazo[1,2-a]pyridine, and    -   2-(2,5-dimethyl-thiophen-3-yl)-imidazo[1,2-a]pyridine.

Preferred compounds of formula I for the above mentioned method oftreatment are also those, in which A is the group

wherein X_(a) and X_(b) are, independently from each other, selectedfrom the group consisting of —CH₂— and —O—; and n is 1 or 2.Thefollowing are examples of these preferred compounds:

-   -   2-indan-5-yl-imidazo[1,2-a]pyridine,    -   2-(2,3-dihydro-benzofuran-5-yl)-imidazo[1,2-a]pyridine, and    -   2-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-imidazo[1,2-a]pyridine.

The present invention is also directed to the following novel compoundsof formula I:

-   -   7-chloro-2-(3,4-dimethyl-phenyl)-imidazo[1,2-a]pyridine,    -   2-(3,4-dimethoxy-phenyl)-imidazo[1,2-a]pyridine,    -   2-(3,4-dimethyl-phenyl)-7-methoxy-imidazo[1,2-a]pyridine,    -   2-(3,4-dimethoxy-phenyl)-7-methoxy-imidazo[1,2-a]pyridine,    -   2-(3,4-dimethyl-phenyl)-7-methyl-imidazo[1,2-a]pyridine,    -   2-(3-bromo-4-fluoro-phenyl)-imidazo[1,2-a]pyridine,    -   2-(4-benzyloxy-3-methoxy-phenyl)-imidazo[1,2-a]pyridine,    -   2-indan-5-yl-imidazo[1,2-a]pyridine,    -   2-(3-bromo-phenyl)-imidazo[1,2-a]pyridine,    -   2-(3-iodo-phenyl)-imidazo[1,2-a]pyridine,    -   2-(3-methyl-phenyl)-imidazo[1,2-a]pyridine,    -   2-benzo[b]thiophen-3-yl-imidazo[1,2-a]pyridine,    -   2-(3-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine,    -   2-(2,3-dihydro-benzofuran-5-yl)-imidazo[1,2-a]pyridine,    -   2-(3-fluoro-phenyl)-imidazo[1,2-a]pyridine,    -   2-(3,4-dimethyl-phenyl)-7-ethyl-imidazo[1,2-a]pyridine,    -   2-(5-methyl-thiophen-2-yl)-imidazo[1,2-a]pyridine,    -   2-(2,5-dimethyl-thiophen-3-yl)-imidazo[1,2-a]pyridine, and    -   2-(3,4-dimethoxy-phenyl)-6-methyl-imidazo[1,2-a]pyridine.

The present invention also includes pharmaceutical compositionscontaining a therapeutically effective amount of one or more of thesenovel compounds, namely

-   -   7-chloro-2-(3,4-dimethyl-phenyl)-imidazo[1,2-a]pyridine,    -   2-(3,4-dimethoxy-phenyl)-imidazo[1,2-a]pyridine,    -   2-(3,4-dimethyl-phenyl)-7-methoxy-imidazo[1,2-a]pyridine,    -   2-(3,4-dimethoxy-phenyl)-7-methoxy-imidazo[1,2-a]pyridine,    -   2-(3,4-dimethyl-phenyl)-7-methyl-imidazo[1,2-a]pyridine,    -   2-(3-bromo-4-fluoro-phenyl)-imidazo[1,2-a]pyridine,    -   2-(4-benzyloxy-3-methoxy-phenyl)-imidazo[1,2-a]pyridine,    -   2-indan-5-yl-imidazo[1,2-a]pyridine,    -   2-(3-bromo-phenyl)-imidazo[1,2-a]pyridine,    -   2-(3-iodo-phenyl)-imidazo[1,2-a]pyridine,    -   2-(3-methyl-phenyl)-imidazo[1,2-a]pyridine,    -   2-benzo[b]thiophen-3-yl-imidazo[1,2-a]pyridine,    -   2-(3-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine,    -   2-(2,3-dihydro-benzofuran-5-yl)-imidazo[1,2-a]pyridine,    -   2-(3-fluoro-phenyl)-imidazo[1,2-a]pyridine,    -   2-(3,4-dimethyl-phenyl)-7-ethyl-imidazo[1,2-a]pyridine,    -   2-(5-methyl-thiophen-2-yl)-imidazo[1,2-a]pyridine,    -   2-(2,5-dimethyl-thiophen-3-yl)-imidazo[1,2-a]pyridine, or    -   2-(3,4-dimethoxy-phenyl)-6-methyl-imidazo[1,2-a]pyridine,    -   and a pharmaceutically acceptable carrier.

The compounds of formula I and their pharmaceutically acceptable saltsare, as already mentioned above, metabotropic glutamate receptorantagonists and can be used for the treatment or prevention of mGluR5receptor mediated disorders, such as acute and/or chronic neurologicaldisorders, cognitive disorders and memory deficits, as well as acute andchronic pain. Treatable neurological disorders are for instanceepilepsy, schizophrenia, anxiety, acute, traumatic or chronicdegenerative processes of the nervous system, such as Alzheimer'sdisease, senile dementia, Huntington's chorea, ALS, multiple sclerosis,dementia caused by AIDS, eye injuries, retinopathy, idiopathicparkinsonism or parkinsonism caused by medicaments as well as conditionswhich lead to glutamate-deficient functions, such as e.g. muscle spasms,convulsions, migraine, urinary incontinence, nicotine addiction,psychoses, opiate addiction, anxiety, vomiting, dyskinesia anddepression. Other treatable indications are restricted brain functioncaused by bypass operations or transplants, poor blood supply to thebrain, spinal cord injuries, head injuries, hypoxia caused by pregnancy,cardiac arrest and hypoglycaemia.

The compounds of formula I or pharmaceutically acceptable salts thereofare especially useful as analgesics. Treatable kinds of pain includeinflammatory pain such as arthritis and rheumatoid disease, vasculitis,neuropathic pain such as trigeminal or herpetic neuralgia, diabeticneuropathy pain, causalgia, hyperalgesia, severe chronic pain,post-operative pain and pain associated with various conditions likecancer, angina, renal or billiay colic, menstruation, migraine and gout.

The pharmacological activity of the compounds of the present inventionwas tested using the following methods:

-   -   cDNA encoding rat mGlu 5a receptor was transiently transfected        into EBNA cells using a procedure described by E. -J. Schlaeger        and K. Christensen (Transient gene expression in mammalian cells        grown in serum-free suspension culture, Cytotechnology 1999, 30,        71-83). [Ca²⁺]i measurements were performed on mGlu 5a        transfected EBNA cells after incubation of the cells with Fluo        3-AM (obtainable by FLUKA, 0.5 μM final concentration) for 1        hour at 37° C. followed by 4 washes with assay buffer (DMEM        supplemented with Hank's salt and 20 mM HEPES. [Ca²⁺]i        measurements were done using a fluorometric imaging plate reader        (FLIPR, Molecular Devices Corporation, La Jolla, Calif., USA).        When compounds were evaluated as antagonists they were tested        against 10 μM glutamate as agonist.

The inhibition (antagonists) curves were fitted with a four parameterlogistic equation giving IC₅₀, and Hill coefficient using the iterativenon linear curve fitting software Origin (Microcal Software Inc.,Northampton, Mass., USA).

The compounds of the present invention are mGluR 5a receptorantagonists. In Table I the activities of compounds of formula I asmeasured in the assay described above are shown:

TABLE I Ex. Activity [μM] 1 0.1 2 1.88 3 6.8 4 0.14 5 3.3 6 0.037 7 0.288 0.69 9 0.83 10 0.93 11 0.95 12 0.97 13 1.23 14 1.55 15 1.66 16 2.76 172.79 18 2.86 19 3.41 20 3.64 21 6.13 22 7.5 23 8.77 24 0.58 25 1.65 268.3 27 0.99 28 10 29 10

The affinity of compounds of formula I to the central benzodiazepinereceptors in vitro was also tested using standard methods as for exampledescribed in Nature 1981, 294, 763-765 and J. Neurochemistry 1981, 37,714-722. According to these methods, the inhibition of the binding oftritiated flumazenil to the specific benzodiazepine receptors in thecortex of rats by the respective test substances is determined and theinhibition dissociation constant (Ki) of each test compound isdetermined according to the method of Cheng & Prusoff (1973).2-(3,4-Dimethyl-phenyl)-imidazo[1,2-a]pyridine hydrochloride was testedaccording to this method and showed a pKi (negative logarithm of the Ki)of 5.2, i.e. the compound does not possess good affinity towards thebenzodiazepine receptors. The fact that the compounds of formula I ofthe present invention do not possess good affinity to benzodiazepinereceptors is surprising when the results for the cited referencepresented above (in paragraph [0005]) forN,N,6-trimethyl-2-(4-methylphenyl)-imidazo[1,2-a]pyridine-3-acetamideare considered. The compound referenced in paragraph [0005] possessesagonist properties at central benzodiazepine receptors, but does notpossess the affinity toward the mGluR5 receptor that is seen with thecompounds of formula 1 of the present invention.

The compounds of formula I and pharmaceutically acceptable salts thereofcan be used in the form of pharmaceutical compositions Thepharmaceutical compositions can be administered orally, e.g. in the formof tablets, coated tablets, dragées, hard and soft gelatine capsules,solutions, emulsions or suspensions. The administration can also beeffected rectally, e.g. in the form of suppositories, or parenterally,e.g. in the form of injection solutions.

The compounds of formula I and pharmaceutically acceptable salts thereofcan be processed with pharmaceutically inert, inorganic or organiccarriers for the production of pharmaceutical compositions. Lactose,corn starch or derivatives thereof, talc, stearic acid or its salts andthe like can be used, for example, as such carriers for tablets, coatedtablets, dragées and hard gelatine capsules. Suitable carriers for softgelatine capsules are, for example, vegetable oils, waxes, fats,semi-solid and liquid polyols and the like; depending on the nature ofthe active substance no carriers are, however, usually required in thecase of soft gelatine capsules. Suitable carriers for the production ofsolutions and syrups are, for example, water, polyols, sucrose, invertsugar, glucose and the like. Adjuvants, such as alcohols, polyols,glycerol, vegetable oils and the like, can be used for aqueous injectionsolutions of water-soluble salts of compounds of formula I, but as arule are not necessary. Suitable carriers for suppositories are, forexample, natural or hardened oils, waxes, fats, semi-liquid or liquidpolyols and the like.

In addition, the pharmaceutical preparations can contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,masking agents or antioxidants. They can also contain still othertherapeutically valuable substances.

As mentioned earlier, pharmaceutical compositions containing a effectiveamount of compound of formula I or pharmaceutically acceptable saltsthereof and a therapeutically inert carrier are also an object of thepresent invention, as is a process for the production of suchmedicaments which comprises bringing one or more compounds of formula Ior pharmaceutically acceptable salts thereof and, if desired, one ormore other therapeutically valuable substances into a galenical dosageform together with one or more therapeutically inert carriers.

The dosage can vary within wide limits and will, of course, be fitted tothe individual requirements in each particular case. In general, thetherapeutically effective dosage for oral or parenteral administrationis between 0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/kg/day beingpreferred for all of the indications described. The daily dosage for anadult human being weighing 70 kg accordingly lies between 0.7-1400 mgper day, preferably between 7 and 700 mg per day.

The compounds of formula I and pharmaceutically acceptable salts thereofcan be prepared by methods well known to those of ordinary skill in theart. For example, compounds of formula I can be obtained by reacting acompound of the formula

with an α-bromo ketone of formula

wherein R¹, R² and A are as defined before, and if desired, converting acompound of formula I into a pharmaceutically acceptable salt.

This reaction is for example described in J. Org. Chem. 1954, 19,1370-1374 or in J. Heterocyclic Chem. 1988, 25, 129-137. Thecyclocondensation of 2-amino pyridines with α-bromo ketones is carriedout in a polar solvent like ethanol and heated under reflux conditionsfor several hours or, alternatively, the reactants are dissolved in asolvent like acetone at room temperature.

The preparation of compounds of formula II is well known to thoseskilled in the art and some of the compounds of formula II arecommercially available. Reviews for the synthesis of 2-aminopyridinescan be found in M. T. Leffler, Organic Reactions, Vol. 1, Ed. R. Adams,J. Wiley and Sons, NY, 1942, Ch. 4, pp. 91-104, or in A. S. Tomcufcik,L. N. Starker, The Chemistry of Heterocyclic Compounds, Pyridine and itsDerivatives, Part 3, Ed. E. Klingsberg, Interscience, NY, 1962, Ch. IX,pp. 1-177, or in E. F. V. Scriven, Comprehensive Heterocyclic Chemistry,Vol. 2, Part 2A, Eds. A. J. Boulton and A. McKillop, Pergamon Press, NY,1984, Ch. 2.05, pp. 165-314. For instance, these compounds can beprepared by the Chichibabin reaction involving the reaction of asubstituted pyridine derivative with sodium amide or sodium amide in thepresence of a substituted amine to yield a 2-aminopyridine derivative offormula II.

The compounds of formula III are also commercially available or can beeasily prepared by the method as described in J. Chem. Soc., PerkinTrans. 1, 1999, 2425-2427. For example,2-bromo-1-(3-bromo-4-fluoro-phenyl)-ethanone,1-(4-benzyloxy-3-methoxy-phenyl)-2-bromo-ethanone,2-bromo-1-indan-5-yl-ethanone, 2-iodo-1-(3-bromo-phenyl)-ethanone,2-bromo-1-m-tolyl-ethanone,2-bromo-1-(3-trifluoromethyl-phenyl)-ethanone,2-bromo-1-(2,3-dihydro-benzofuran-5-yl)-ethanone,2-bromo-1-(3,4-dimethyl-phenyl)-ethanone,2-bromo-1-(5-methyl-thiophen-2-yl)-ethanone,2-bromo-1-(3-methoxy-phenyl)-propan-1-one,2-bromo-1-(2,5-dimethyl-thiophen-3-yl)-ethanone,2-bromo-1-(3,4-dimethoxy-phenyl)-ethanone,2-bromo-1-(4-morpholin-4-yl-3-nitro-phenyl)-ethanone and2-bromo-1-(3,4-dimethyl-phenyl)-hexan-1-one are obtained in analogy tothis method by α-bromination of the appropriate commercially availableacetophenones using polymer-supported pyridinium bromide perbromide(PSPBP) in toluene at 10° C. (scheme 1).

The preparation of compounds of formula I, especially of the novelcompounds

-   -   7-chloro-2-(3,4-dimethyl-phenyl)-imidazo[1,2-a]pyridine,    -   2-(3,4-dimethoxy-phenyl)-imidazo[1,2-a]pyridine,    -   2-(3,4-dimethyl-phenyl)-7-methoxy-imidazo[1,2-a]pyridine,    -   2-(3,4-dimethoxy-phenyl)-7-methoxy-imidazo[1,2-a]pyridine,    -   2-(3,4-dimethyl-phenyl)-7-methyl-imidazo[1,2-a]pyridine,    -   2-(3-bromo-4-fluoro-phenyl)-imidazo[1,2-a]pyridine,    -   2-(4-benzyloxy-3-methoxy-phenyl)-imidazo[1,2-a]pyridine,    -   2-indan-5-yl-imidazo[1,2-a]pyridine,    -   2-(3-bromo-phenyl)-imidazo[1,2-a]pyridine,    -   2-(3-iodo-phenyl)-imidazo[1,2-a]pyridine,    -   2-(3-methyl-phenyl)-imidazo[1,2-a]pyridine,    -   2-benzo[b]thiophen-3-yl-imidazo[1,2-a]pyridine,    -   2-(3-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine,    -   2-(2,3-dihydro-benzofuran-5-yl)-imidazo[1,2-a]pyridine,    -   2-(3-fluoro-phenyl)-imidazo[1,2-a]pyridine,    -   2-(3,4-dimethyl-phenyl)-7-ethyl-imidazo[1,2-a]pyridine,    -   2-(5-methyl-thiophen-2-yl)-imidazo[1,2-a]pyridine,    -   2-(2,5-dimethyl-thiophen-3-yl)-imidazo[1,2-a]pyridine, or    -   2-(3,4-dimethoxy-phenyl)-6-methyl-imidazo[1,2-a]pyridine, is        described in more detail in the following examples. The examples        are to be considered as being illustrative and representative of        the invention, but not as limiting the scope of the present        invention.

Pharmaceutically acceptable salts of compounds of formula I can bemanufactured readily according to methods known in the art and takinginto consideration the nature of the compound to be converted into asalt. Inorganic or organic acids such as, for example, hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid orcitric acid, formic acid, fumaric acid, maleic acid, acetic acid,succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonicacid and the like are suitable for the formation of pharmaceuticallyacceptable salts of basic compounds of formula I. Compounds whichcontain the alkali metals or alkaline earth metals, for example sodium,potassium, calcium, magnesium or the like, basic amines or basic aminoacids are suitable for the formation of pharmaceutically acceptablesalts of acidic compounds. Unless stated to the contrary, all of thecompounds listed in the examples were prepared and characterized asdescribed.

EXAMPLE 1 7-Chloro-2-(3,4-dimethyl-phenyl)-imidazo[1,2-a]pyridine

To a stirred solution of 2-amino-4-chloro-pyridine (0.39 g, 3.03 mmol)in ethanol (25 ml) was added 3,4-dimethyl-phenacylbromide (0.69 g, 3.03mmol). The reaction mixture was stirred under reflux conditions for 16h, poured into sat. NaHCO₃ solution (70 ml) and extracted withdichloromethane (70 ml). The combined organic layers were washed withbrine (70 ml), dried (MgSO₄) and evaporated to give the crude product asa brown solid (0.84 g). Further purification by column chromatography onsilica gel (ethyl acetate/toluene 1:9) and crystallization from ethylacetate/hexane yielded the title compound (0.54 g, 69%) as a pale yellowsolid, m.p. 144° C. and MS: m/e=256.2 (M⁺).

EXAMPLE 2 2-(3,4-Dimethoxy-phenyl)-7-methyl-imidazo[1,2-a]pyridine

The title compound, pale yellow solid, m.p. 163° C. and MS: m/e=268.1(M⁺), was prepared in accordance with the general method of example 1from 2-amino-4-methyl-pyridine and 3,4-dimethoxy-phenacylbromide.

EXAMPLE 3 2-(3,4-Dimethoxy-phenyl)-imidazo[1,2-a]pyridine

The title compound, pale yellow solid, m.p. 96° C. and MS: m/e=254.1(M⁺), was prepared in accordance with the general method of example 1from 2-amino-pyridine and 3,4-dimethoxy-phenacylbromide.

EXAMPLE 4 2-(3,4-Dimethyl-phenyl)-7-methoxy-imidazo[1,2-a]pyridine

The title compound, pale yellow solid, m.p. 175° C. and MS: m/e=252.2(M⁺), was prepared in accordance with the general method of example 1from 2-amino-4-methoxy-pyridine and 3,4-dimethyl-phenacylbromide.

EXAMPLE 5 2-(3,4-Dimethoxy-phenyl)-7-methoxy-imidazo[1,2-a]pyridine

The title compound, pale yellow solid, m.p. 142° C. and MS: m/e=284.1(M⁺), was prepared in accordance with the general method of example 1from 2-amino-4-methoxy-pyridine and 3,4-dimethoxy-phenacylbromide.

EXAMPLE 6 2-(3,4-Dimethyl-phenyl)-imidazo[1,2-a]pyridine Hydrochloride

The title compound was obtained in analogy to the method as described inpatent application WO 00/08021.

EXAMPLE 7 2-(3,4-Dimethyl-phenyl)-7-methyl-imidazo[1,2-a]pyridine

The title compound, solid, MS: m/e=237.0 (M+H⁺), was obtained in analogyto the general method of example 1.

EXAMPLE 8 2-(3-Bromo-4-fluoro-phenyl)-imidazo[1,2-a]pyridine

In analogy to the method as described in J. Heterocyclic Chem. 1988, 25,129-137, 2-Bromo-1-(3-bromo-4-fluoro-phenyl)-ethanone (89 mg, 0.3 mmol)and 2-Aminopyridine (28 mg, 0.3 mmol) were dissolved in 2 ml of acetoneand shaken overnight. The solvent was evaporated and and the residue wasdissolved in 1 ml of DMF. The title compound (m/e=292.6, [M+H⁺]) wasisolated from this solution by HPLC chromatography (YMC CombiPrep C18column 50×20 mm, solvent gradient 10-95% CH₃CN in 0.1% TFA(aq) over 6.0min, λ=230 nm, flow rate 40 ml/min).

EXAMPLE 9 2-(4-Benzyloxy-3-methoxy-phenyl)-imidazo[1,2-a]pyridine

The title compound, MS: m/e=330.9 (M+H⁺), was prepared in accordancewith the general method of example 8 from1-(4-Benzyloxy-3-methoxy-phenyl)-2-bromo-ethanone.

EXAMPLE 10 2-Indan-5-yl-imidazo[1,2-a]pyridine

The title compound, MS: m/e=234.8 (M+H⁺), was prepared in accordancewith the general method of example 8 from 2-Bromo-1-indan-5-yl-ethanone.

EXAMPLE 11 2-(3-Bromo-phenyl)-imidazo[1,2-a]pyridine

The title compound, MS: m/e=274.5 (M+H⁺) was prepared in accordance withthe general method of example 8 from2-Bromo-1-(3-bromo-phenyl)-ethanone.

EXAMPLE 12 2-(3-Iodo-phenyl)-imidazo[1,2-a]pyridine

The title compound, MS: m/e=320.7 (M+H⁺), was prepared in accordancewith the general method of example 8 from2-Iodo-1-(3-bromo-phenyl)-ethanone.

EXAMPLE 13 2-(3-Chloro-phenyl)-imidazo[1,2-a]pyridine

The title compound, MS: m/e=228.5 (M+H⁺), was prepared in accordancewith the general method of example 8 from2-Chloro-1-(3-bromo-phenyl)-ethanone.

EXAMPLE 14 2-(3-Methyl-phenyl)-imidazo[1,2-a]pyridine

The title compound, MS: m/e=208.8 (M+H⁺), was prepared in accordancewith the general method of example 8 from 2-Bromo-1-m-tolyl-ethanone.

EXAMPLE 15 2-Benzofuran-2-yl-imidazo[1,2-a]pyridine

The title compound, MS: m/e=234.8 (M+H⁺), was prepared in accordancewith the general method of example 8 from1-Benzofuran-2-yl-2-bromo-ethanone.

EXAMPLE 16 2-Benzo[b]thiophen-3-yl-imidazo[1,2-a]pyridine

The title compound, MS: m/e=250.8 (M+H⁺), was prepared in accordancewith the general method of example 8 from1-Benzo[b]thiophen-3-yl-2-bromo-ethanone.

EXAMPLE 17 2-(3-Trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine

The title compound, MS: m/e=262.7 (M+H⁺) was prepared in accordance withthe general method of example 8 from2-Bromo-1-(3-trifluoromethyl-phenyl)-ethanone.

EXAMPLE 18 2-(2,3-Dihydro-benzofuran-5-yl)-imidazo[1,2-a]pyridine

The title compound, MS: m/e=236.8 (M+H⁺), was prepared in accordancewith the general method of example 8 from2-Bromo-1-(2,3-dihydro-benzofuran-5-yl)-ethanone.

EXAMPLE 19 2-(3-Fluoro-phenyl)-imidazo[1,2-a]pyridine

The title compound, MS: m/e=212.7 (M+H⁺), was prepared in accordancewith the general method of example 8 from2-Bromo-1-(3-fluoro-phenyl)-ethanone.

EXAMPLE 20 2-(3,4-Dimethyl-phenyl)-7-ethyl-imidazo[1,2-a]pyridine

The title compound, MS: m/e=250.8 (M+H⁺), was prepared in accordancewith the general method of example 8 from2-Bromo-1-(3,4-dimethyl-phenyl)-ethanone and 4-Ethyl-pyridin-2-ylamine.

EXAMPLE 21 2-(5-Methyl-thiophen-2-yl)-imidazo[1,2-a]pyridine

The title compound, MS: m/e=215.0 (M+H⁺), was prepared in accordancewith the general method of example 8 from2-Bromo-1-(5-methyl-thiophen-2-yl)-ethanone.

EXAMPLE 22 7-Methyl-2-phenyl-imidazo[1,2-a]pyridine

The title compound, MS: m/e=209.0 (M+H⁺), was obtained by the method asdescribed in J. Med. Chem. 1998, 41(25), 5108-5112.

EXAMPLE 23 2-(4-Methyl-phenyl)-imidazo[1,2-a]pyridine

The title compound, MS: m/e=209.2 (M+H⁺), was obtained by the method asdescribed in patent application EP 0 533 058.

EXAMPLE 24 2-(2,5-Dimethyl-thiophen-3-yl)-imidazo[1,2-a]pyridine

The title compound, MS: m/e=229.0 (M+H⁺), was prepared in accordancewith the general method of example 8 from2-bromo-1-(2,5-dimethyl-thiophen-3-yl)-ethanone.

EXAMPLE 25 2-(3-Methoxy-phenyl)-imidazo[1,2-a]pyridine

The title compound, MS: m/e=224.8 (M+H⁺), was prepared in accordancewith the general method of example 8 from2-bromo-1-(3-methoxy-phenyl)-ethanone.

EXAMPLE 26 2-(3,4-Dimethoxy-phenyl)-6-methyl-imidazo[1,2-a]pyridine

The title compound, MS: m/e=269.2 (M+H⁺), was prepared in accordancewith the general method of example 8 from 5-methyl-pyridin-2-ylamine and2-bromo-1-(3,4-dimethoxy-phenyl)-ethanone.

EXAMPLE 27 2-(2,3-Dihydro-benzo[14]dioxin-6-yl)-imidazo[1,2-a]pyridine

The title compound, MS: m/e=253.0 (M+H⁺), was prepared in accordancewith the general method of example 8 from2-bromo-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethanone.

EXAMPLE 28 6-Methyl-2-(4-methyl-phenyl)-imidazo[1,2-a]pyridine

The title compound, MS: m/e=223.0 (M+H⁺), was obtained by the method asdescribed in patent application EP 1 038 875.

EXAMPLE 29 2-(3-Nitro-phenyl)-imidazo[1,2-a]pyridine

The title compound, MS: m/e=240.2 (M+H⁺), was prepared in accordancewith the general method of example 8 from2-bromo-1-(3-nitro-phenyl)-ethanone.

EXAMPLE A

Tablets of the following composition are produced in a conventionalmanner:

mg/Tablet Active ingredient 100 Powdered. lactose 95 White corn starch35 Polyvinylpyrrolidone 8 Na carboxymethylstarch 10 Magnesium stearate 2Tablet weight 250

EXAMPLE B

Tablets of the following composition are produced in a conventionalmanner:

mg/Tablet Active ingredient 200 Powdered. lactose 100 White corn starch64 Polyvinylpyrrolidone 12 Na carboxymethylstarch 20 Magnesium stearate4 Tablet weight 400

EXAMPLE C

Capsules of the following composition are produced:

mg/Capsule Active ingredient 50 Crystalline. lactose 60 Microcrystallinecellulose 34 Talc 5 Magnesium stearate 1 Capsule fill weight 150

The active ingredient having a suitable particle size, the crystallinelactose and the microcrystalline cellulose are homogeneously mixed withone another, sieved and thereafter talc and magnesium stearate areadmixed. The final mixture is filled into hard gelatine capsules ofsuitable size.

1. A method of treatment or prevention of a mGluR5 receptor mediateddisease comprising administering, to a person in need of such treatment,a therapeutically effective amount of a compound of formula

wherein R¹ is selected from the group consisting of hydrogen,(C₁₋₆)-alkyl, halogen, hydroxy and R² is selected from the groupconsisting of hydrogen, (C₁₋₆)-alkyl, halogen, hydroxy and(C₁₋₆)-alkoxy; A is unsubstituted aryl or aryl substituted with at leastone substituent selected from the group consisting of (C₁₋₆)-alkyl,halogen, halogen-(C₁₋₆)-alkyl, hydroxy, (C₁₋₆)-alkoxy, benzyloxy, amino,(C₁₋₆)-alkylamino, di-(C₁₋₆)-alkyl-amino, arylamino, diarylamino andnitro, or is unsubstituted heteroaryl or heteroaryl substituted with atleast one substituent selected from the group consisting of(C₁₋₆)-alkyl,halogen, halogen-(C₁₋₆)-alkyl, hydroxy, (C₁₋₆)-alkoxy, benzyloxy, amino,(C₁₋₆)-alkylamino, di-(C₁₋₆)-alkyl-amino, arylamino, diarylamino andnitro, or is the group

wherein X_(a) and X_(b) are, independently from each other, selectedfrom the group consisting of —CH₂— and —O—; and n is 1 or 2; or apharmaceutically acceptable salt thereof.
 2. A method according to claim1, wherein the MGLU mediated disease is selected from the groupconsisting of acute and/or chronic neurological disorders, cognitivedisorders and memory deficits.
 3. The method according to claim 1wherein the MGLUR5 mediated disease is acute and/or chronic pain.
 4. Themethod according to claim 1 wherein the MGLUR5 mediated disease isAlzheimer's disease.
 5. The method according to claim 1 wherein theMGLUR5 mediated disease is Parkinson's disease.
 6. A method according toclaim 1, wherein the mGluR5 mediated disease is selected from the groupconsisting of senile dementia, ischemia, Huntington's chorea,amyotrophic lateral sclerosis and multiple sclerosis, and psychiatricdiseases.
 7. A method according to claim 6, wherein the psychiatricdisease is selected from the group consisting of psychosis, epilepsy,schizophrenia.
 8. A method according to claim 7 wherein the psychiatricdisease is anxiety and depression.
 9. The method according to claim 1,comprising administering an effective amount of a compound of formula Iwherein A is unsubstituted aryl or aryl substituted with at least onesubstituent selected from the group consisting of (C₁₋₆)-alkyl, halogen,halogen-(C₁₋₆)-alkyl, hydroxy, (C₁₋₆)-alkoxy, benzyloxy, amino,(C₁₋₆)-alkylamino, di-(C₁₋₆)-alkyl-amino, arylamino, diarylamino andnitro, and R¹ and R² are as defined in claim
 1. 10. The method accordingto claim 9, wherein A is unsubstituted phenyl or phenyl substituted withat least one substituent selected from the group consisting of(C₁₋₆)-alkyl, halogen, halogen-(C₁₋₆)-alkyl, hydroxy, (C₁₋₆)-alkoxy,benzyloxy, amino, (C₁₋₆)-alkylamino, di-(C₁₋₆)-alkyl-amino, arylamino,diarylamino and nitro.
 11. The method according to claim 10, wherein Ais phenyl substituted with at least one substituent selected from thegroup consisting of (C₁₋₆)-alkyl, halogen, halogen-(C₁₋₆)-alkyl,hydroxy, (C₁₋₆)-alkoxy, benzyloxy, amino, (C₁₋₆)-alkylamino,di-(C₁₋₆)-alkyl-amino, arylamino, diarylamino and nitro.
 12. The methodaccording to claim 11, wherein the compound is selected from the groupconsisting of 2-(3-chloro-phenyl)-imidazo[1,2-a]pyridine,7-methyl-2-phenyl-imidazo[1,2-a]pyridine,2-(4-methyl-phenyl)-imidazo[1,2-a]pyridine,2-(3-methoxy-phenyl)-imidazo[1,2-a]pyridine,6-methyl-2-(4-methyl-phenyl)-imidazo[1,2-a]pyridine, and2-(3-nitro-phenyl)-imidazo[1,2-a]pyridine.
 13. The method according toclaim 10, wherein A is phenyl substituted with at least two substituentsselected from the group consisting of (C₁₋₆)-alkyl, halogen,halogen-(C₁₋₆)-alkyl, hydroxy, (C₁₋₆)-alkoxy, benzyloxy, amino,(C₁₋₆)-alkylamino, di-(C₁₋₆)-alkyl-amino, arylamino, diarylamino andnitro.
 14. The method according to claim 13, wherein the compound isselected from the group consisting of2-(3,4-dimethoxy-phenyl)-7-methyl-imidazo[1,2-a]pyridine, and2-(3,4-dimethyl-phenyl)-imidazo[1,2-a]pyridine hydrochloride.
 15. Themethod according to claim 1, wherein A is unsubstituted heteroaryl orheteroaryl substituted with at least one substituent selected from thegroup consisting of (C₁₋₆)-alkyl, halogen, halogen-(C₁₋₆)-alkyl,hydroxy, (C₁₋₆)-alkoxy, benzyloxy, amino, (C₁₋₆)-alkylamino,di-(C₁₋₆)-alkyl-amino, arylamino, diarylamino and nitro.
 16. The methodaccording to claim 15, wherein the compound is2-benzofuran-2-yl-imidazo[1,2-a]pyridine.
 17. The method according toclaim 1, wherein A is the group

wherein X_(a), X_(b) are, independently from each other, —CH₂— or —O—;and n is 1 or
 2. 18. The method according to claim 17, wherein thecompound is2-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-imidazo[1,2-a]pyridine.